We propose to continue our study of the membrane basis for susceptibility to anticancer therapy. This application is to investigate the role of fish oil polyunsaturated fatty acids in cancer biology and therapy. There is evidence that membrane polyunsaturates of the omega-3 class, which are abundant in marine oils, can inhibit the growth of malignant neoplasms. In contradistinction, those of omega-6 class may actually promote growth. Our paradigm is the experimental insertion of fatty acids of various comparative classes into the membranes of cancer cells. We will utilize both dietary and tissue culture models. The insertion is fairly rapid and dose dependent (with plateau). The substituted membranes have no apparent major disruption of membrane structure based on preliminary evidence. The biochemical (lipid composition) and physical results (membrane order) of the substitution on plasma and intracellular membranes will be delineated. Studies on both a murine and human neoplasm are included. The effects of the substitution on the biology (self- renewal, differentiation) will be examined. Most importantly, we will investigate the potential of dietary fatty acid alteration as a therapeutic adjunct to cancer chemotherapy (Adriamycin and the membrane active drug ET-18-OCH3) and hyperthermia. Clinical contexts will be pursued, but not forced. We will also continue our investigation of the mechanisms by which membrane polyunsaturated fatty acid enrichment augments the sensitivity of leukemia cells to Adriamycin and this will include a multifaceted investigation of the role of oxygen radicals and subsequent lipid peroxidation. The studies should help understand the role of membranes in the altered biology of cancer, and the application of fatty acid alteration as adjunct to cancer therapy as part of a multimodal approach. The results could lead to application to human cancer since there are dietary methods for enriching membranes clinically.